Method and apparatus for sterilizing a heat sensitive fluid

ABSTRACT

Methods and apparatus for sterilizing heat sensitive fluids are provided. The methods include providing a first heat sensitive fluid component, providing a second fluid component, heating the second fluid component to a temperature greater than a predetermined sterilizing temperature, mixing the first heat sensitive fluid component with the heated second fluid component to heat the first heat sensitive fluid components and provide a mixed fluid at a temperature at least up to the predetermined sterilizing temperature, and maintaining the mixed fluid at that temperature for a predetermined sterilizing period. Apparatus for carrying out this method is also provided.

FIELD OF INVENTION

The present invention relates to a method and apparatus for producing asterile medical solution. More specifically, the present inventionrelates to a method and apparatus for producing a sterile medicalsolution comprising a heat sensitive component, such as glucose.

BACKGROUND OF THE INVENTION

Medical solutions intended for mammals, specifically for use in humans,are required to be sterile before being infused or applied to themammal.

One available method for sterilizing a solution is to heat the solutionto a sterilizing temperature and to hold the solution at the sterilizingtemperature during a sterilizing time period. To obtain a sterilemedical solution intended for infusion, the solution is normally heatedin an autoclave to 121° C. for 20 minutes to thereby produce saidsterile medical solution. After the sterilizing time has elapsed, thesolution should be cooled to a physiologically acceptable temperaturebefore infusion.

Known methods and apparatus for sterilizing a solution are disclosed,for example, in British Patent Applications Nos. 1,450,030; 1,504,334;and 2,034,584, and in U.S. Pat. No. 5,603,894. These prior artpublications describe the preparation of a medical solution startingfrom tap water and producing pure water by means of a reverse osmosisdevice, mixing a concentrate with the pure water to produce anon-sterile medical solution, passing the non-sterile medical solutionthrough an on-line autoclave and delivering the sterile medical solutionto a recipient, such as a storage bag or a patient.

In the prior art, the complete medical solution is first prepared in anon-sterile condition and then passes through an autoclave. If themedical solution comprises heat sensitive components, these must not beexposed to too high a temperature. Normally, the temperature isincreased up to the sterilizing temperature and the medical solution ismaintained at the sterilizing temperature for a sterilizing time period.If the temperature is 121° C., which is normal in an autoclave, thesterilizing time is 20 minutes to obtain a sterilizing dose, F₀, of 20minutes, as discussed below. Since the sterilizing effect isapproximately exponential, an increase of the temperature by 10° C.means a lowering of the sterilizing time by ten times. If a sterilizingtemperature of 131° C. is used, the sterilizing time should be 2minutes, and if a sterilizing temperature of 141° C. is used, thesterilizing time should be 12 seconds, in order to obtain a sterilizingeffect, F₀, of 20 minutes.

If the medical solution comprises a heat sensitive component, likeglucose, that component will deteriorate during the heat treatment. Anexample of a medical solution containing a heat sensitive component is adialysis fluid for peritoneal dialysis (PD). The decomposition or heatdeterioration starts at a much lower temperature than the sterilizingtemperature and is also present at room temperature. In order tosafeguard the heat sensitive material, very short heating and coolingperiods are desired so that the time/temperature profile becomes more orless rectangular. This is of greater importance if high sterilizingtemperatures and short sterilization times are used.

It is known to produce sterile medical solutions by including themedical solution in a bag and placing the bag inclusive of the medicalsolution, in an autoclave for heating and sterilization.

A variant of this method is described in international Application No.WO 93/09820, in which the medical solution is divided into two portions,one comprising glucose at high concentration and the other comprisingthe rest of the solution. The double bag is heat sterilized in anautoclave. Shortly before use, the contents of the two chambers aremixed to produce the sterile medical solution. In this way, the heatsensitive component, glucose, can be autoclaved under more appropriateconditions, such as at a low pH of approximately 3.2, and at a highconcentration of approximately 50%, i.e. 500 grams of glucose per literof glucose solution.

A variant of the same methods is described in International ApplicationNo. WO 97/05852 disclosing a three-chamber-bag, in which two of thechambers comprise glucose solution and the third chamber comprises therest of the solution. The glucose chambers may also include ioniccomponents, such as calcium, magnesium and sodium.

A further variant is described in International Application No. WO99/27885.

In the aforementioned concepts, the glucose portion is sterilizedseparately from the remaining portion of the solution. However, in orderto fully sterilise the large compartment, the small glucose compartmentmay be over sterilized, resulting in deterioration of the heat sensitivecomponent. A remedy for that problem is described in Swedish patentapplication No. 9803627-0, filed at the Swedish Patent Office on Oct.23, 1998.

The problem of deterioration of a substance during autoclaving is alsorecognised in other fields of use, such as the production of sterilemilk products. In order to obtain rapid heating and cooling of theproduct, it is not sufficient to use heat transfer by means of a heattransferring surface, like a heat exchanger. Instead, the product ismixed with steam at a predetermined temperature and pressure to condensethe steam in the milk product. The milk product is sterilized byretention in a holding zone for a certain time period and at atemperature of from about 120 to 150° C., and is then transferred to aflash cooling step, in which water is evaporated in an evaporationchamber to rapidly cool the product. Such a process is described in, forexample, International Application No. WO 98/07328.

DISCLOSURE OF INVENTION

One object of the present invention is to provide a method and apparatusfor producing a sterile medical solution having a gentle treatment ofthe heat sensitive component.

Another object of the present invention is to provide a method andapparatus in which inexpensive heaters and heat exchangers can be used.

A third object of the present invention is to provide a method andapparatus for sterilizing a medical solution in which thetime/temperature profile for heating the heat sensitive component isessentially rectangular.

SUMMARY OF THE INVENTION

In accordance with the present invention, these and other objects havenow been realized by the invention of a method for sterilizing a heatsensitive fluid comprising providing a first heat sensitive fluidcomponent, providing a second fluid component, heating the second fluidcomponent to a first temperature, the first temperature being greaterthan a predetermined sterilizing temperature, mixing the first heatsensitive fluid component with the heated second fluid component,whereby the first heat sensitive fluid component is heated and theheated second fluid component is cooled, and a mixed fluid is providedat a second temperature, the second temperature being at least thepredetermined sterilizing temperature, and maintaining the mixed fluidat the second temperature for a predetermined sterilizing period,whereby a predetermined sterilizing dose is obtained for delivery to arecipient. Preferably, the method includes controlling the heating ofthe second fluid component to the first temperature to ensure that themixed fluid reaches the second temperature.

In accordance with one embodiment of the method of the presentinvention, the method includes cooling the mixed fluid.

In accordance with another embodiment of the method of the presentinvention, the first heat sensitive fluid component comprises glucose ora glucose polymer.

In accordance with another embodiment of the method of the presentinvention, the second fluid component comprises water. Preferably, thesecond fluid component includes electrolytes, such as sodium chloride,calcium chloride, magnesium chloride, potassium chloride, sodiumbicarbonate, or sodium lactate.

In accordance with another embodiment of the method of the presentinvention, the method includes preheating the first heat sensitive fluidcomponent.

In accordance with another embodiment of the method of the presentinvention, the method includes maintaining the first heat sensitivefluid component and the second fluid component under a predeterminedpressure sufficient to prevent boiling of the first heat sensitive fluidcomponent and the second fluid component. Preferably, providing of thefirst heat sensitive fluid component and providing of the second fluidcomponent comprises providing flows of these fluid components. In apreferred embodiment, the flow of the first heat sensitive fluidcomponent comprises a first flow rate and the flow of the second fluidcomponent comprises a second flow rate, the second flow rate beinggreater than the first flow rate.

In accordance with another embodiment of the method of the presentinvention, the method includes determining the first and second flowrates by means of a weighing device or a flow meter, and maintaining thefirst heat sensitive fluid component and the second fluid component atthe predetermined pressure by means of a pump.

In accordance with another embodiment of the method of the presentinvention, the heat sensitive fluid component comprises a complex fluidcomprising a plurality of first fluid components including the firstheat sensitive fluid component, and the method includes sequentiallysterilizing the plurality of first fluid components. In a preferredembodiment, the method includes providing a plurality of sources ofconcentrate fluid components for each of the plurality of first fluidcomponents, providing a source of the second fluid component, the secondfluid component comprising water, pumping one of the plurality ofsources of the concentrate fluid components so as to increase thepressure thereof, pumping the water so as to increase the pressurethereof, and repeating the method for each of the plurality of firstfluid components. Preferably, the method includes preheating each of theplurality of first fluid components before the mixing with the heatedsecond fluid component. Most preferably, the preheating comprises heatexchanging each of the plurality of the first fluid components with thepredetermined sterilized dose. Preferably, the preheating comprisesinitially heating the second fluid component by heat exchange with thepredetermined sterilized dose, and further preheating the second fluidcomponent to the first temperature by means of a separate heater,preferably comprising an electric heater. Preferably, the methodincludes controlling the further preheating of the second fluidcomponent by means of a temperature sensor downstream of the maintainingof the mixed fluid at the second temperature, whereby the secondtemperature is maintained at the at least the predetermined sterilizingtemperature.

In accordance with another embodiment of the method of the presentinvention, the method includes dissolving at least one powderedsubstance in the second fluid component to provide at least one of thefirst heat sensitive fluid components and the second fluid component.

In accordance with another embodiment of the method of the presentinvention, the method includes providing a third heat sensitive fluidcomponent, and mixing the first heat sensitive fluid component and thethird heat sensitive fluid component with the heated second fluidcomponent. Preferably, the third heat sensitive fluid componentcomprises water and at least one amino acid.

In accordance with the present invention, an apparatus has also beendiscovered for sterilizing a heat sensitive fluid comprising a firstvessel containing a first heat sensitive fluid component, a secondvessel containing a second fluid component, a first heater for heatingthe second fluid component to a first temperature, the first temperaturebeing greater than a predetermined sterilizing temperature, mixing meansfor mixing the first heat sensitive fluid component with the secondfluid component to obtain a mixed fluid at a second temperature at leastequal to the predetermined sterilizing temperature, and residence meansfor maintaining the mixed fluid at the second temperature for apredetermined sterilizing period, whereby a sterilized fluid is providedfor delivery to a recipient. Preferably, the apparatus includes acontroller for controlling the first heater to obtain the firsttemperature.

In accordance with one embodiment of the apparatus of the presentinvention, the apparatus includes a cooler for cooling the mixed fluid.

In accordance with another embodiment of the apparatus of the presentinvention, the first heat sensitive fluid component comprises glucose ora glucose polymer.

In accordance with another embodiment of the apparatus of the presentinvention, the second fluid component comprises water. Preferably, thesecond fluid component includes an electrolyte, including sodiumchloride, calcium chloride, magnesium chloride, potassium chloride,sodium bicarbonate or sodium lactate.

In accordance with another embodiment of the apparatus of the presentinvention, the apparatus includes a preheater for preheating the firstheat sensitive fluid component.

In accordance with another embodiment of the apparatus of the presentinvention, the apparatus includes pressurizing means for maintaining thefirst heat sensitive fluid component and the second fluid component at apredetermined pressure to prevent the first heat sensitive fluidcomponent and the second fluid component from boiling.

In accordance with another embodiment of the apparatus of the presentinvention, the first heat sensitive fluid component and the second fluidcomponent comprise fluid flows. Preferably, the fluid flow of the firstheat sensitive fluid component has a first flow rate and the fluid flowof the second fluid component has a second flow rate, the second flowrate being greater than the first flow rate. Preferably, the apparatusincludes flow rate determining means for determining the first andsecond flow rates, the pressurizing means comprising a pump. Preferably,the flow rate determining means comprises a weighing device or a flowmeter.

In accordance with another embodiment of the apparatus of the presentinvention, the first heat sensitive fluid component comprises aplurality of first fluid components including the first heat sensitivefluid component, and the apparatus includes means for sequentiallysterilizing each of the plurality of first fluid components and thesecond fluid component. In a preferred embodiment, the means forsequentially sterilizing includes supply means for supplying theplurality of first fluid components, the first vessel comprising aplurality of containers for concentrates of the plurality of first fluidcomponents, the second vessel comprising an inlet for the second fluidcomponent, a concentrate pump for pumping one of the plurality of firstfluid components from one of the plurality of containers whereby thepressure of the one of the first fluid components is increased, a waterpump for pumping the second fluid component, the second fluid componentcomprising water, whereby the pressure of the second fluid component isincreased, the heater comprising a water heater for heating the secondfluid component to the first temperature, the mixing means comprising amixer for mixing the one of the plurality of first fluid components andthe heated second fluid component to provide said mixed fluid, theresidence means comprising means for maintaining the mixed fluid at thefirst temperature for a predetermined sterilizing period to provide asterilized dose for delivery to a recipient, and including control meansfor controlling and repeating the sequential sterilizing of each of theplurality of first fluid components to provide a final sterilizedcomplex fluid. Preferably, the apparatus includes preheating means forpreheating the one of the plurality of first fluid components. Mostpreferably, the apparatus includes a heat exchanger for recovering heatfrom the sterilized dose, the heat exchanger preheating the second fluidcomponent by heat exchange with the sterilized dose, and the apparatusincluding a heater for heating the second fluid component to the firsttemperature. Most preferably, the apparatus includes a temperaturesensor downstream of the residence means for controlling the heater,whereby the first temperature comprises a temperature at leastsufficient to constitute the sterilizing temperature.

In accordance with another embodiment of the apparatus of the presentinvention, at least one of the first and second vessels includes atleast one powdered substance for dissolution in water to provide atleast one of the first and second fluids.

In accordance with another embodiment of the apparatus of the presentinvention, the apparatus includes a third vessel for containing a thirdheat sensitive fluid component. Preferably, the third heat sensitivefluid component comprises water and at least one amino acid.

According to the present invention, a method of sterilizing a heatsensitive fluid is provided, comprising providing the fluid as a firstheat sensitive component and a second less heat sensitive component;heating the second component to a first temperature higher than apredetermined sterilizing temperature; mixing the first component withthe second component to thereby heat the first component and cool thesecond component, whereby the mixed components obtain a mixingtemperature, which is at least equal to the sterilizing temperature;maintaining the mixed components at substantially the sterilizingtemperature during a sterilization time period, so that a predeterminedsterilization dose is obtained; and delivering the mixed component to arecipient.

Preferably, the first temperature is controlled to obtain a mixingtemperature, which is at least equal to the sterilizing temperature.Moreover, it is preferred to cool the mixed components before deliveryto the recipient.

The first heat sensitive component may comprise glucose or a glucosepolymer and the second less heat sensitive component may comprise water.More specifically, the second component may include electrolytes,selected from the group of substances comprising: sodium chloride,calcium chloride, magnesium chloride, potassium chloride, sodiumbicarbonate and sodium lactate.

It may be advantageous to preheat the first component. Normally, thetemperature is above the boiling temperature at normal atmosphericpressure and, thus, the first and second components are maintained at ahigh pressure sufficient to prevent boiling.

In one embodiment, the first and second components are provided as flowsof fluid, in which the flow rate of the second component is larger thanthe flow rate of the first component.

In order to separate the flow rate determination from the pressurisingmeans, the flow rates are determined with a pair of scales or a flowmeter, and the pressure is provided by a separate pump.

In one embodiment of the present invention, the complex fluid is dividedinto several fluid components, which are sterilized separately, asdescribed above, and sequentially and then mixed with the complex fluid.This may be performed by providing sources of concentrated fluidcomponents and pure water; pumping a first concentrated fluid from thesources of concentrated fluids, to increase the pressure thereof;pumping pure water to increase the pressure thereof, and heating thepure water to the first temperature; mixing the first concentrate andheated pure water and maintaining the mixed fluids at a sterilizingtemperature for a sterilizing time to effect sterilization; deliveringthe sterilized and diluted concentrate fluid to a recipient; repeatingthe above method steps for each of the concentrated fluid components, toprovide the final complex fluid for the recipient. The concentratedfluid may be preheated before being mixed with the heated water, forexample by a heat exchanger by heat recovery from the sterilized fluid,which is cooled thereby.

The second fluid may be preheated by heat recovery in a heat exchangerfrom the sterilized fluid, which is thereby cooled, and further heatedto the first temperature by a separate heating device, such as anelectric heater. The heating device may be controlled by a temperaturesensor positioned downstream of the maintaining step, to ensure that asterilizing temperature is obtained.

BRIEF DESCRIPTION OF THE DRAWINGS

Further objects, advantages and features of the present invention willappear from the following detailed description of several embodimentsshown in the drawings, as follows:

FIG. 1 is a top, elevational, schematic view of one embodiment of anapparatus for sterilizing a heat sensitive fluid according to thepresent invention;

FIG. 2 is a top, elevational, schematic view of another embodiment of anapparatus according to the present invention;

FIG. 3 is a top, elevational schematic view of a portion of yet anotherembodiment of an apparatus according to the present invention;

FIG. 4 is a side, elevational, cross-sectional view of a heatsterilisable connector used in the apparatus according to FIG. 2;

FIG. 5 is a top, elevational, schematic view of yet another embodimentof the apparatus according to the present invention;

FIG. 6 is a side, elevational, schematic view of one embodiment of acycler which may be connected to the apparatus according to FIGS. 2 or4;

FIG. 7 is a graphical representation of a time diagram of the fluidflows in the cycler according to FIG. 6; and FIG. 8 is a side,elevational, schematic view of another embodiment of a cycler for use inconnection with the apparatus of the present invention.

DETAILED DESCRIPTION

The fluid to be sterilized according to the present invention comprisesa first non-heat-sensitive portion and a second heat sensitive portion.According to the present invention, these two portions are deliveredseparately to the sterilizing device into two separate inlets 1 and 2.

With reference to FIG. 1, the first non-heat-sensitive component, whichmay comprise sodium chloride dissolved in water, is enclosed in a vessel3 connected to the inlet 1. The second heat sensitive component, whichmay comprise glucose, is enclosed in a vessel 4 connected to the inlet2. The fluid components are preferably provided at a temperature atwhich each component is relatively stable, such as room temperature.

The first fluid portion from vessel 3 provided to inlet 1 is impelled bya first pump 5 to a heater 6, in which the first fluid portion is heatedto a first high temperature. The second fluid portion is impelled by asecond pump 7 and mixed with the first fluid portion at a mixing point 8disposed downstream of the heater 6. During the mixing, the second fluidportion is rapidly heated to a sterilizing temperature, while the firstfluid portion is cooled to the same sterilizing temperature. The secondfluid portion does not make direct contact with the heater surface andso damage is minimised.

In order to promote rapid mixing, the fluids are impelled at suchconditions that turbulent flow prevails at least after the mixing point8. In addition, flow mixing means may be arranged in the flow path, suchas at the mixing point 8 or in the flow path downstream of mixing point8. Such flow mixing means may be flanges or wings in the flow path.

The mixed fluid portions pass through a sterilizing tube section 9 whichis dimensioned to provide a predetermined resident or sterilizing timeperiod for the mixed fluids at the sterilizing temperature. The tubesection may be insulated as indicated by box 10 in order to maintain themixed fluids at the sterilizing temperature for the sterilizing timeperiod. After the sterilizing time period, the mixed fluids are sterile,since the second fluid portion has been subjected to the sterilizingtemperature during a sterilizing time period and the first fluid portionhas been exposed to a still higher temperature for a still longer timeperiod, thus being oversterilized.

The sterilizing dose is a function of temperature and time and isdefined according to the formula: F₀ = ∫₀^(t)10^((T − 121)/10)t

in which

F₀=the sterilization dose, in minutes

T=temperature

t=time

If the sterilizing temperature is 121° C. and the time is 20 minutes, asterilization dose, F₀, of 20 minutes is obtained. If the sterilizingtemperature is 141° C. and the time is 12 seconds, a sterilization doseF₀ of 20 minutes is also obtained. A sterilizing dose F₀ of 20 minutesis considered sufficient, however, in certain applications, asterilizing dose F₀ of 10 minutes or even lower may be sufficient.

In the above example, the first fluid portion may comprise sodiumchloride at a concentration of 150 mM, sodium lactate at a concentrationof 38.8 mM, magnesium chloride at a concentration of 0.56 mM and calciumchloride at a concentration of 1.89 mM. The second fluid portion maycomprise glucose at a concentration of 40%, i.e. 400 g glucose per literof solution. The first fluid portion flow rate is 45 ml/min and thesecond fluid portion flow rate is 5 ml/min. The resulting mixture hasthe following composition: sodium chloride 135 mM, sodium lactate 35 mM,magnesium chloride 0.5 mM, calcium chloride 1.7 mM and glucose 4%. Thefirst fluid portion is heated from 20° C. to 155° C. by the heater 6.The second fluid portion is heated from 20° C. to 141° C. during mixing,while the first fluid portion is cooled from 155° C. to 141° C. Theresident or sterilizing time period is 12 seconds, resulting in asterilizing dose, F₀, of 20 minutes. The resulting sterilized fluidmixture is cooled by a cooler 13 and delivered to an outlet 11 andcollected in a vessel 12. A pump 20 or other device may be arranged tocontrol the flow to the vessel 12. The sterile fluid may be used as aperitoneal dialysis solution to be delivered to the peritoneal cavity ofa patient.

Other medical fluids may be produced by the device according to thepresent invention, such as hemodialysis solutions, infusion solutionsused in hemodiafiltration or hemofiltration, replacement fluids forinfusion in the blood, wound irrigation solutions, rinsing solutions,etc. Moreover, nutrition solutions often comprises amino acids, whichare heat sensitive, and glucose, which is heat sensitive, and cannot besterilized together with amino acids. Certain drugs, such as insulin,may be produced or included in a fluid administered to a patient, andthe drug component may be heat sensitive. Certain medical fluidscomprise peptides, proteins or fragments thereof, which normally areheat sensitive. Preservation fluids for blood component handling mayalso comprise heat sensitive components, at least glucose. In certaincases, glucose is replaced with or complemented with glucose polymers,di-sacharides, tri-sacharides etc. Certain carboxylic acids are heatsensitive and may be included in such fluids. Solutions comprisingcalcium or magnesium ions and carbonate or bicarbonate ions mayprecipitate upon exposure to a sterilizing temperature, and need to besterilized with the carbonate or bicarbonate separate from the calciumor magnesium containing solution.

In order to control the above procedure, one or more temperature sensorsare provided. A first temperature sensor 14 may be arranged immediatelydownstream of the heater 6 to determine the temperature of the firstfluid portion after heating. A second temperature sensor 15 may bearranged between the second inlet 2 and the mixing point 8 to determinethe temperature of the second fluid before mixing. A third temperaturesensor 16 may be arranged downstream of the mixing point to determinethe mixing temperature. A fourth temperature sensor may be arrangeddownstream of the sterilizing section 9 to determine the sterilizingtemperature. A fifth temperature sensor 18 may be arranged downstream ofcooler 13 to determine the temperature of the fluid delivered to vessel12. Not all of these five temperature sensors are needed, so that one ormore thereof may be excluded.

A control processor 19 may be arranged to control the sterilizing deviceaccording to the present invention. As shown in FIG. 1, the fivetemperature sensors are connected to the processor as well as the pumps,5, 7 and 20, to provide measurements of the temperatures and flow rates.The pumps, 5, 7 and 20, may be volumetric pumps, also acting as flowmeters. Alternatively, separate flow meters may be provided. Theprocessor controls the heater 6 to provide the required temperaturedownstream of the heater, as measured by temperature sensor 14, toprovide the sterilizing temperature after mixing, as measured bytemperature sensors, 16 and 17. The processor calculates the residencetime in the sterilizing section 9 based on the flow rates of pumps, 5and 7, and the known volume of the sterilizing section 9. Finally, theprocessor may determine the obtained sterilizing dose, F₀.

The control processor 19 may obtain all necessary information in orderto calculate the sterilizing effect from the flow rates of pumps 5 and 7and the temperature of sensor 17.

As also shown in FIG. 1, the fluids provided to inlets 1 and 2 may bepreheated by preheaters, 21 and/or 22.

Since the sterilizing apparatus shown in FIG. 1 is intended to heat thefluids to temperatures well above 100° C., it is required to keep thefluids from boiling. This may be done by enclosing the entire apparatusin an enclosure 23, as shown by broken lines in FIG. 1, and raising thepressure inside the enclosure to a pressure sufficient to preventboiling, such as from about 3 to 6 Bar absolute pressure.

It is known that glucose decomposes when exposed to heat, and is thus aheat sensitive component of the fluid. Glucose also decomposes duringstorage. It is known that several factors influence the decomposition ofglucose, among which are pH, temperature, time, glucose concentrationand mixing with certain ionic components. Glucose decomposes intocomponents, some of which may be more or less toxic or are able toinduce toxic reactions by including precursors for such reactions. Ifthe resulting fluid is to be used as a medical fluid for infusion into ahuman being or other mammal, the toxic components or precursors shouldbe minimised.

In order to sterilise the fluid it is necessary to expose the fluid tosterilizing conditions. There are several methods available, such asheat sterilization (autoclaving), filter sterilization and othermethods. The present invention is limited to heat sterilization.

During heat sterilization, it is known that decomposition of glucose canbe minimised if glucose is sterilized during a short time at a hightemperature. The rationale is that the decomposition reaction is lesssensitive to high temperature than in the sterilizing reaction.

In order to minimise the decomposition before sterilization, it isadvantageous to store the fluid at a low pH and at a high concentration,which is suggested according to the present invention. The pH may befrom about 2.6 to 5.0, and preferably about 3.2. The concentration maybe above 15%, or above 20%, with 40% to 50% being preferred, calculatedas weight of glucose per liter solution.

The sterilization may take place during a short time and at a pH ofbelow about 5.5 and at a final dilution concentration. It is believedthat the short time is of greater importance than the other factors foravoiding decomposition into toxic components of glucose during thesterilization process.

It is also recognised that glucose may decompose into precursors for AGE(advanced glucosylation end products). When a glucose solutioncomprising precursors for AGE contacts proteins in the body, anon-enzymatic reaction takes place, resulting in AGE formation. The longterm effect of AGE is still not well known. Gentle heat sterilization ofglucose as suggested in the present invention is expected to reduce thelevel of glucose degradation products of the type of AGE precursors.

An alternative embodiment of the present invention is shown in FIG. 2.In this embodiment the sterilizing device according to the presentinvention is integrated in a PD monitor which is arranged to provide aPD solution to a patient. The PD solution is prepared from twoconcentrates provided in two concentrate bags 51 and 52 and connected toconcentrate input connectors 56 and 57, and a supply of pure water, forexample provided from a reverse osmosis (RO) unit 53 connected to awater input connector 58 for connection to a potable water supply. Thesterilized PD fluid is delivered to a PD cycler 55, which is, in turn,connected to a PD fluid output connector 59 for delivery to the patient.

Each of the three input connectors and the output connector is arrangedas a heat sterilisable connector device as shown in more detail in FIG.4. Such a heat sterilisable connector device 30 is described inInternational Application No. WO 96/05883 and comprises a spike 31opening into a bore 32 in a housing 33. The bore is arranged to receivea connector 35 connected to a vessel or bag, for example comprising theconcentrate. The connector has a shape which is complementary to thebore, such as cylindrical, and which may be inserted into the bore toseal the bore by means of an O-ring 37. The connector is furtherprovided with a membrane 35 a which is pierceable by spike 31. Theconnector 35 is operable by a piston 39 to be pushed into the bore intoa first position sealing the bore 32. The piston is operable by a motor38 operating a screw and nut arrangement 38 a or any other suitabledriving device, like a pneumatically or hydraulically operated device.

During operation, the connector 35 is inserted in the bore 32 intoco-operation with the O-ring 37. A rinsing, disinfecting and/orsterilizing fluid is circulated through the spike 31 into the bore 32and out through a side opening 36 in the bore. The spike, bore and themembrane of the connector are thus rinsed, disinfected and/orsterilized. When the rinsing, disinfecting and/or sterilizing operationis finished, the piston 39 pushes the connector 35 further into the bore32 so that the spike 31 penetrates the membrane 35 a to therebyestablish a connection between the spike and the vessel connected to theconnector 35. At the same time, the connector seals off the side opening36 and an area around the spike 31.

The connector device 30 may also be used without inserting a connector35 by passing the piston 39 into the bore 32 into co-operation with theO-ring seal 37 to establish a flow path through spike 31 into sideopening 36.

Returning now to FIG. 2, each of the inputs, 56, 57 and 58, and theoutput 59 is arranged as a connector device 30 of FIG. 4. Input 56 isarranged to connect a first concentrate bag 51 to a first metering pump60 and input 57 is arranged to connect a second concentrate bag 52 to asecond metering pump 61. Input 58 is connected to RO-unit 53 and a thirdpump 62 is arranged to pump pure water from RO-unit 53.

Pumps 62 and 60 are driven to mix the concentrate from bag 51 with purewater from RO-unit 53 to provide a desired concentration. A conductivitycell 63 may be arranged to measure the conductivity of the mixture andmay control pump 60 and/or 62 to obtain the required conductivity andthus the desired concentration. Pump 62 is preferably driven to providea constant flow of, for example, 54 ml/min and at the same time increasethe pressure to from about 3 to 6 Bar absolute pressure, to avoidboiling during sterilization. The fluid provided so far is the firstheat-insensitive fluid mentioned above.

The first fluid passes through a first heat exchanger 64 comprising aprimary circuit 64 a for heating the first fluid, for example from about20° C. to 100° C. Then, the first fluid passes through a heater 65, suchas an electric heater powered by an electric power supply 66, to heatthe first fluid to a temperature of 155° C.

The second, heat sensitive, fluid from bag 52 is pumped by pump 61, at aflow rate of 6 ml/min to a mixing point 67 immediately downstream ofheater 65 to mix with the first fluid. The second fluid is thus rapidlyheated from room temperature to a temperature of 141° C. by being mixedwith the hot first fluid, which at the same time cools down to 141° C.

Then, the mixed fluids pass through a sterilizing unit 68 comprising atube 68 a of a length suitable for providing a residence time, givingthe required sterilizing time, such as 12 seconds. The tube is embeddedin an insulating material 68 b to minimize temperature decrease duringthe residence time.

Immediately downstream of the sterilizing unit 68 is a temperaturesensor 69, which controls the power supply 66 so that the temperature isthe desired sterilizing temperature, such as 141° C.

Pump 61 is controlled in order to deliver the heat sensitive fluid inthe amount desired. For example, if the heat sensitive fluid is glucoseat a concentration of 40%, the flow rate should be 6 ml/min to give afinal concentration of 4% if the first flow rate is 54 ml/min. If aconcentration of 1.5% is desired, the flow rate should be 2.1 ml/min andif a concentration of 2.5% should be obtained, the flow rate should be3.6 ml/min. In each case, the temperature sensor adjusts the powersupply to heat the first fluid to a suitable temperature so that thesterilizing temperature is obtained.

Downstream of the sterilizing unit 68, the now sterilized fluid entersthe secondary circuit 64 b of the heat exchanger 64 to rapidly decreasethe temperature of the sterilized fluid, for example to 60° C. Then, thesterilized fluid passes a flow restrictor 70 to decrease the pressure toclose to atmospheric pressure. Preferably, the flow restrictor 70 iscontrolled by a pressure sensor 71, so that the pressure before therestrictor is the desired pressure to prevent boiling, such as 6 Barabsolute pressure.

From the flow restrictor 70, the sterilized fluid is delivered to theoutput 59, which is connected to a PD cycler 55. A pressure relief valve72 is arranged to connect the sterilized fluid to a waste 73 if thepressure of the fluid exceeds a predetermined value, such as 150 mmHgabove atmospheric pressure.

The PD cycler may be of the type described in International ApplicationNo. WO 95/20985, comprising a pressure chamber. A disposable line set isconnected between the outlet connector and the patient and comprises aheater bag and a drain bag, a drain line and a supply line. The heaterbag and a drain bag are arranged on a weighing device, such as a pair ofscales. Four valves in a valve unit are arranged to operate on the drainand supply lines. Finally, the line set comprises a PD connector forconnection to a catheter into the peritoneal cavity of the patient. ThePD fluid from outlet 59 is supplied to the heater bag by means of thevalve unit until the scales indicate that the heater bag has been filledto a predetermined volume, such as 3 liters. Then the patient is drainedby exposing the pressure chamber to a subpressure to withdraw fluid inthe peritoneal cavity of the patient out through the open valve unitinto the drain bag. The combined weight of heater bag and drain bag isweighed and the drain phase is terminated when it is determined that thedrain flow rate is below a predetermined limit or a drain time haselapsed. The drain flow rate is determined by means of the weighingdevice. Then, the pressure chamber is exposed to an overpressure and thevalve unit is opened to allow the fresh sterilized PD fluid to flow intothe peritoneal cavity of the patient. The flow rate and the deliveredfluid volume is monitored, and the fill phase is terminated when adesired fill volume has been delivered. The temperature of the heaterbag is controlled by a heating device and temperature sensor so that thefluid delivered has a temperature of about 37° C. Finally, the drain bagis emptied to the waste by opening the valve unit and exposing thepressure chamber to an overpressure.

When the patient has been exposed to a fluid exchange as describedabove, the PD fluid is left in the peritoneal cavity for a dwell timeuntil the next exchange cycle. During the dwell time period, thesterilizing device provides new sterile fluid to the heater bag. Ittakes about 33 minutes to produce a fill volume of 2 liters if sterilefluid is produced at 60 ml/min.

It may be desirable to include a cooler 82 after the flow restrictor 70in order to further decrease the temperature before delivering the fluidto the heater bag. The cooler may be a Peltier cooler or a heatexchanger of conventional design, using cold water or a cooling mediumas heat energy absorption medium. A cooler 91, such as a Peltier cooler,may alternatively or additionally be placed after residence device 68and before heat exchanger 64, in order to rapidly cool the heatsensitive mixture to a safe temperature, such as from 141° C. to 120° C.In this manner, the heat sensitive component is rapidly heated from roomtemperature to sterilization temperature of 141° C. at mixing point 67,is maintained at the sterilizing temperature during 12 seconds byresidence device 68 and is then rapidly cooled to 120° C. by Peltiercooler 91 and then further cooled to room temperature in the slightlyslower heat exchanger 64

The sterilizing device needs to be disinfected at suitable intervals,for example once per day or once per week. For that purpose, the sideopenings of the connector devices, 56, 57, 58 and 59, are used. The sideopening 83 of RO inlet 58 is connected to the side opening 82 of outlet59 through a line 84. The side opening 85 of first inlet 56 is connectedto the flow line 86 between RO inlet 58 and the pump 62 through a line87. The side opening 88 of second inlet 57 is connected to the line 89between heater 65 and sterilizing unit 68 through a line 90.

During disinfection, the sterilizing device is filled with pure waterobtained from the RO-unit. Then, connectors, 57, 58 and 59, aredisconnected from the respective sources and the piston is arranged inthe position in conjunction with the O-ring, in order to seal the bore32 of the connector opening, (see FIG. 4).

Thus, the RO-inlet connector 58 and the outlet connector 59 areconnected through line 84 and side openings 82 and 83. The second inletconnector 57 is in the same position so that a circulating path isobtained by means of pump 61, line segment 89, line 90, side opening 88and inlet 57. A disinfecting solution is provided in a vessel connectedto the first inlet 56. The disinfecting fluid may be sodium carbonate,citric acid or any other known disinfection fluid. Pumps 62 and 61 areoperated to circulate the water in the circuits. Finally, pump 60 isoperated to infuse disinfection fluid into the water until a sufficientdisinfectant concentration has been obtained. The surplus water isrejected by means of relief valve 72 to the waste 73. Pump 62 circulatesthe disinfection fluid through the complete sterilization device and theoutlet 59 is connected to the inlet 58 through line 84 to complete thecircuit. The disinfection fluid may be left in the machine until thenext use. Before the next use, the machine is rinsed with pure waterthrough inlet 58 from the source of RO-water.

Descaling with citric acid or other descaling agent is performed in thesame manner.

In order to avoid dripping from the connectors, the inlet connectors,56, 57 and 58, and the outlet connector 59 are positioned at the highestposition of the flow path and at the same level.

The machine may be emptied by opening all inlets, 56, 57 and 58, and theoutlet 59 and by opening the relief valve 72, which is positioned at thelowest point of the flow path, and by allowing air to enter all linesand devices.

During chemical disinfection and/or descaling, the heater 65 may beturned off or adjusted to heat the fluid to a low temperature. The flowrestrictor 70 may be opened.

In heat sterilization, the fluid in the entire circuit is heated to 121°C. and circulated for at least 20 minutes to obtain sterilization of theentire circuit. In this case, pressure relief valve 72 is operated topermit a pressure of 2 Bar, thereby preventing boiling of the water inthe circuit at 121° C.

The same or a similar procedure may be used for sterilizing the flowpath of the sterilizing device. The fluid circuit is arranged for atreatment with all connectors inserted in respective bore 32 in thenon-engaged position. The circuit is filled with water, which iscirculated by pump 62. Flow restrictor 70 is opened and relief valve 72is adjusted to a pressure of from about 2 to 3 Bar absolute pressure.First inlet connector 56 is operated to connect the vessel 51 to thecircuit. Then, pump 60 is operated to introduce some fluid (electrolytefluid) in the circuit until the pressure reaches about 2 to 3 Barabsolute pressure. Since the fluid circuit is relatively non-compliant,the volume of fluid introduced is very small. Then, the heater isactivated to heat the water present in the circuit to a temperature of121° C. and the circulation continues for 20 minutes or longer, untilsterilization is obtained. Pump 61 is operated simultaneously tosterilise the circuit comprising inlet connector 57.

After sterilization has been obtained, RO inlet 58 is activated toconnect RO-unit 53 to the circuit and at the same time disconnect bypassline 84. Pump 60 is stopped, and heater 65 is activated. Flow restrictor70 is activated and pressure relief valve 72 is adjusted to the normalvalue of 150 mmHg overpressure. Thus, sterile water is produced anddelivered to the waste 73 by means of relief valve 72. Then, the secondinlet is activated to connect vessel 52 and pumps, 60 and 61, areoperated to provide a PD fluid. When stable conditions are obtained, theoutlet 59 is activated to deliver sterilized fluid to the heater bag.

During the drain and fill phases of the PD cycler, the sterilizingdevice may continue to produce PD fluid. However, since the valve unitis closed, the PD fluid produced is directed to the waste 73 by means ofrelief valve 72. Since the drain and fill phases may last up to 20minutes or more, a considerable amount of PD fluid is wasted. Tominimise such waste, pumps 60 and 61 may be stopped during the periodswhen the heater bag is not being filled, and the sterilizing device isonly producing and wasting sterile water.

The first and/or second concentrates may comprise the same substances orcomponents as mentioned above, however, with the contents of the firstvessel 51 concentrated by omitting some of the water. The contents ofthe first vessel may be concentrated, for example, about 30 to 40 times.In an alternative embodiment, the PD fluid is intended to comprisebicarbonate instead of or in addition to lactate. Calcium cannot beincluded in the same vessel as bicarbonate, because of the risk ofprecipitation of calcium carbonate. In that case, the calcium chloridemay be included in the second vessel 52 in a suitable concentration. Thecalcium concentration will then be proportional to the glucoseconcentration, which may result in a calcium neutral PD fluid. Anotheradvantage of including the calcium ions in the second vessel is thatscaling of the pipe system is avoided before the mixing point 67, andthe requirement for descaling would decrease.

Each of the sterilizable connectors may be replaced by a conventionalconnector device and a three way valve of conventional type, as shown inmore detail in FIG. 3, which shows an alternative embodiment of thepresent invention.

FIG. 3 shows an alternative design of a mixing system delivering themixed fluids in parallel through the residence device. FIG. 3 shows onlythe right-hand portion of FIG. 2 to the right of pump 62 and pressuresensor 70. The left-hand portion may be identical to the embodimentshown in FIG. 2. The same components as in FIG. 2 have received the samereference numerals, but 100 is added to the reference numbers. Thus,there is shown a heat exchanger 164 comprising a primary circuit 164 aand a secondary circuit 164 b and a pump device 164 c. An electrolytesolution or pure water is conducted through line 189 through heatexchanger primary circuit 164 a and a second heater 165, for example anelectric heater controlled by a temperature sensor 169.

A first bag 152 a comprising a heat sensitive first component such asglucose is connected by means of a connector 192 a to a three-way valve157 a. The first component passes from the three-way valve 157 a to apump 161 a and further to a mixing point 167 a, in which the firstcomponent is heated to 141° C. by mixture with a heated electrolytecomponent, having a temperature sufficient for promoting such heating bymixing, the temperature being, for example, 155° C. The mixingtemperature is controlled by a temperature sensor 169 a, which operatesa throttle valve 193 a disposed before the mixing point 167 a. Bythrottling the valve 193 a, a sufficient flow rate for obtaining saidtemperature is adjusted.

A second bag 152 b comprising a heat sensitive second component, such asamino acids, is connected by means of a connector 192 b to a three-wayvalve 157 b. The second component passes from the three-way valve 157 bto a pump 161 b and further to a mixing point 167 b, in which the secondcomponent is heated to 141° C. by mixture with a heated electrolytecomponent, having a temperature sufficient for promoting such heating bymixing, the temperature being, for example, 155° C. The mixingtemperature is controlled by a temperature sensor 169 b, which operatesa throttle valve 193 b arranged before the mixing point 167 b. Bythrottling the valve 193 b, a sufficient flow rate for obtaining saidtemperature is adjusted.

The two heat sensitive components heated to sterilizing temperature bymixture with the electrolyte component are handled in parallel in twoseparate lines, 194 a and 194 b, which pass in parallel through theresidence device 168, the pre-cooler 191, if present, and to heatexchanger secondary circuit 164 b. After cooling in the heat exchanger,the two fluids are mixed in a Y-connector 195 before entering therestriction device 70 (see FIG. 2). The bags 152 a and 152 b are weighedand when a sufficient amount of fluid has been taken out from each bag,valve 157 a and/or valve 157 b are switched to stop the flow of firstand/or second components from bags 152 a and 152 b, respectively.

During sterilization, the three-way valves, 157 a and 157 b, areconnected according to the broken lines in FIG. 3, in order to passfluid, by means of pumps, 161 a and 161 b, in the fluid lines to andfrom the three-way valves, 157 a and 157 b, through lines 190 a and 190b.

It can be seen that more than two heat sensitive components may behandled in parallel by adding further bags 152 and further lines 194.The same procedure may be adopted for components which are less heatsensitive, to obtain a simple system, whereby the electrolyte componentmay be replaced with pure water, and thus, the electrolytes may be addedone by one, or several at a time.

A further alternative embodiment of the present invention is shown inFIG. 5. From the left, the device 100 comprises a connector 101 forconnection to a source of pure water, such as an RO-unit (not shown).The device further comprises three concentrate connectors, 102, 103 and104, which may be integrated into a single connector device. Each of theconnectors, 102, 103 and 104, connects to a vessel or bag comprising aconcentrate, such as a first bag 105 comprising a concentratedbicarbonate solution, a second bag 106 comprising electrolytes, such assodium chloride, magnesium chloride, calcium chloride, and sodiumlactate, at a predetermined pH, and a third bag 107 comprising glucoseat a concentration of 50%. The bags include the components necessary forthe final solution, as discussed in more detail below. The componentsare divided into separate bags because they cannot be stored together,or they cannot be sterilized together, or for other reasons.

Alternatively, one or more of the vessels or bags, 105, 106 and 107, maycomprise a powder instead of a solution, in which case appropriatedissolution means may be provided.

Conveniently, the bags, 105, 106 and 107, are combined into a singleassembly. The combined assembly of bags is attached to a weighing device108, so that the weight of the assembly is monitored. The connectors,102, 103 and 104, are attached to the ends of flexible tubes of PVC orother suitable pliable material, so that the connectors and tubes do notsignificantly influence the weight of the assembly. The RO inletconnector 101 is connected to a line system including a first inlet line109. Inlet line 109 is provided with a inlet valve 110, to isolate thedevice 100, if required. Inlet valve 110 is normally closed, but isopened upon activation by a control device 111, shown by broken lines.The control device may be a computer or microprocessor or any othercontrol device. Normally, it is the control computer of the completedevice.

Inlet line 109 further comprises a heater 112 and a temperature sensor113, which operate together to adjust the temperature of incoming purewater to a predetermined temperature of, e.g., 25° C., in order to makethe device independent of incoming water temperature.

Inlet line 109 further comprises a flow meter 114 for measuring thecomplete inlet flow through inlet connector 101, for a purpose to bedescribed later.

Downstream of flow meter 114, inlet line 109 is divided into water line115 and concentrate line 116. Water line 115 comprises a first pump 117for increasing the pressure of the water in water line 115 downstream ofthe pump to a pressure of from about 2 to 6 Bar absolute pressure. Thepressure is measured by a first pressure sensor 118 and monitored by asecond pressure sensor 119. The first pressure sensor 118 is connectedto the control system of computer 111, while the second pressure sensor119 is connected to a parallel supervising system for ensuring thesafety of the system. Several of the sensors are duplicated in thismanner to provide independent data to the supervisory system orprocessor, even if not explicitly indicated in the drawings.

Water line 115 further comprises a valve 120 and a primary circuit of aheat exchanger 121. In the heat exchanger, the water in water line 115is heated from about 25° C. to about 131° C. in heat exchanger 121, at aflow of about 120 ml/min. The temperature of the heated water ismonitored by temperature sensor 122. Finally, water line 115 comprises asecond heater 123, for heating the water to a still higher temperature,such as about 145° C. The hot water is delivered to a mixing point 124.

In concentrate line 116, there is a valve 125 for connecting thenormally closed concentrate line 116 to water line 115. Furtherdownstream, concentrate line 116 comprises three concentrate valves,126, 127 and 128, and a reversible second pump 129. The second pump 129is arranged to withdraw concentrate solutions or fluids from any one ofconcentrate bags, 105, 106 or 107, depending on the positions of thevalves, 126, 127 and 128. The second pump 129 further increases thepressure of the fluid in concentrate line 116 to a pressure of about 2to 6 Bar absolute pressure.

Downstream of second pump 129 is arranged a valve 130, and, theconcentrate fluid is delivered therefrom to a second primary circuit ofheat exchanger 121 in order to preheat the concentrate solution frome.g. room temperature to about 131° C. From heat exchanger 121, theconcentrate solution is delivered to mixing point 124.

Upstream of the second pump 129 is disposed a temperature sensor 131 formeasuring the temperature of the incoming concentrate fluid, anddownstream of the second pump is disposed a pressure sensor 132 formeasuring that sufficient pressure has been obtained. As indicatedabove, these sensors may be duplicated for supervisory purposes.

In mixing point 124, the two fluid lines 115 and 116 are joined so thatthe heated water in line 115 is mixed with preheated concentrate in line116, and the mixture is transported in mixed fluid line 133. Mixed fluidline 133 comprises a residence device 134, normally being a length oftube of a length to produce a predetermined residence time at apredetermined rate of flow to effect sterilization of the fluid in theresidence device 134. The residence device 134 is preceded by atemperature sensor 135 and followed by a temperature sensor 136. Thesetemperature sensors control the heater 123 to ensure that sterilizingconditions are obtained in the residence device 134, such as a minimumtemperature of 141° C. for 12 seconds.

From the residence device 134, the sterilized and mixed fluid is passedto the secondary circuit of heat exchanger 121, at a temperature ofapproximately 141° C. The sterilized fluid is rapidly cooled to about37° C.

Downstream of the heat exchanger, mixed fluid line 133 comprisessterilized fluid at a temperature suitable to be delivered to a patientor a storage bag. The temperature is monitored by a temperature sensor137. Finally, a valve 138, when activated, directs the fluid to anoutlet connector 139, by means of a restrictor device 140, for loweringthe pressure to atmospheric pressure.

The restrictor device may be a small hole in a piece of metal, the holebeing dimensioned to reduce the pressure from 6 Bar to 1 Bar at thedesired flow rate of, for example, 140 ml/min. An alternative designwould be to use a controllable throttle valve, which is controlled bythe processor dependent upon pressure sensor readings. A thirdalternative would be to use a throttle device or the pressure relieftype, which adjust the differential pressure over the throttle device toa predetermined pressure drop, for example, of about 5 Bar. A fourthalternative would be to use a throttle device controlled to deliverfluid at an output pressure of no more than a predetermined safepressure of, for example, 1.25 Bar, in which case the pumps are operatedto ensure that the pressure before the throttle device is sufficientlyhigh, for example about 6 Bar.

It is noted that the on-line autoclave as described is always operatedat a predetermined minimal flow rate of not less than a predeterminedflow rate, for example 120 ml/min, in order to ensure that the autoclaveis maintained sterile. As soon as the flow rate drops below thepredetermined minimum flow rate, the sterility conditions may behampered or the autoclave may not be controlled to operate at propertemperatures. The autoclave may be designed to operate different flowrates above the minimum flow rate. In order to always maintain a minimalflow rate, any excess fluid produced is sacrificed to the waste.

If the mixed and sterilized fluid cannot be delivered out by means ofthe output connector 139, a valve 141 is activated to deliver the fluidto a sump or waste through a waste line 142. Waste line 142 furthercomprises a primary circuit of a second heat exchanger 143, a pressuresensor 144, a restrictor device 145 and a valve 146 until the fluid isdelivered to the waste 147. A temperature sensor 148 arranged upstreamof heat exchanger 143, and another temperature sensor 149 arrangeddownstream of valve 146, are used to measure the temperatures of thewaste fluid.

The device according to FIG. 5 may be operated in different modes. Onemode of operation will be described below, namely sequential delivery ofthe components of the final fluid. It is, however, understood that thedevice may operate as described in connection with FIG. 2 as well.

In the sequential operation mode, water is first delivered in inlet line109 at a constant rate of 120 ml/min from inlet connector 101, by meansof flow meter 114, in which the flow rate is monitored, and throughwater line 115 and first pump 117 to raise the pressure so that theboiling temperature of the fluid is above the temperature anywhere inthe circuit. If the maximum temperature is about 150° C., the pressureshould be above 4.8 Bar or preferably about 6 Bar absolute pressure. Theexact pressure is dependent on the adjustment and operation ofrestriction device 140. The water further passes the mixing point 124and enters the mixed fluid line 133 and reaches valve 138, which directsthe flow to waste line 142, by means of valve 141, and further to thesump. The outlet connector 139 is connected to a recipient, normally abag, such as a heater bag described below.

When all conditions are checked, and the device delivers sterilizedwater, valve 138 is switched to direct the sterilized water to theoutlet connector 139 by means of restrictor 140.

Substantially at the same time, or shortly thereafter, valve 127 inconcentrate line 116 is opened and concentrate pump 129 is activated,with valve 130 in an open condition, to pump concentrate fluid fromelectrolyte bag 106, by means of heat exchanger 121 to mixing point 124.The concentrate pump 130 is operated to provide a flow rate ofapproximately 20 ml/min. At the same time, the weight of the concentrateassembly is monitored by weighing device 108. If the intention is toprovide 1 liter of final solution and the concentrate fluid in bag 106has a concentration of 1:40, the flow is continued for about 1 minuteand 15 seconds, until the weighing device indicates that a volume of 25ml has left the bag 106, whereby 25 ml is the amount required fromconcentrate bag in 1 liter of final fluid (1:40).

Then, valve 127 is switched off and valve 125 is opened for a shorttime, such as 15 seconds, to rinse the concentrate line 116.

For including the second concentrate, which may be glucose, bag 107 isconnected to the concentrate pump by closing valve 125 and opening valve128. If the glucose concentrate fluid has a concentration of 50%, theconcentrate pump is driven 1 minute per percent concentration to berequired in the final fluid at 20 ml/min. If 4% is required, which isthe maximum contemplated for a PD fluid, the glucose concentrate isdosed in 4 minutes.

After this step, the concentrate line 116 is again rinsed with water,for example for 15 seconds.

Thereafter, the bicarbonate bag 105 is connected. The bicarbonate isnormally stored at a concentration of about 1000 mmol/l. First, valve125 is closed and valve 126 is opened so that concentrate pump 130 pumpsbicarbonate fluid out of bag 105. The flow rate may be the same, 20ml/min, and the mixing and sterilization of bicarbonate fluid isdiscontinued when the weighing device determines that the requiredquantity has been removed from bag 105. If the final solution shouldcontain 15 mmol/l, the concentrate pump is operated for 45 seconds totake 15 ml of concentrated bicarbonate solution out of bag 105.

Finally, the concentrate line is rinsed once again and water isdelivered to the outlet connector, until the final volume of fluid hasbeen delivered to the bag connected at the outlet connector, which isdetermined by flow meter 114 in combination with the weight lossesmeasured by weighing device 108 and calculated into volumes by computer111, taking into account the different densities of the concentratefluids.

This final filling of water also means that the mix of fluid in the bagconnected to the outlet connector is agitated and mixed thoroughly.

During the complete sterilization process described above, valves 138and 141 are maintained in the same position directing all fluid to theoutlet connector 139. Thus, all fluid produced is delivered to thereceiver, thereby minimising the time required for preparation of thecomplete fluid.

In the example above, 1 liter of final solution has been prepared, butin PD it is more normal that 2 liters are generated each time, or anyother volume as required by the user.

It is contemplated that the concentrate fluid bags may includeconcentrate fluid required for a final fluid volume of about 12 to 25liters or more, if required. Then, the above sequence is repeated foreach batch of 2 liters to prepare.

In certain applications for PD, bicarbonate is not used, but lactate isused as the sole buffer. In that case, the third bag in the concentrateassembly is unnecessary, and only two bags may be used. In that case,valve 126 is always closed.

To prepare one batch of 1 liter (1.5% glucose concentration), takesabout 7 minutes and 45 seconds, supposing that the RO unit delivers purewater at 120 ml/min and 25 ml electrolytes, 15 ml bicarbonate and 30 mlglucose are used. Thus, the waiting time between each PD exchange ofabout 2 liters has to be more than 15.5 minutes. This might be limitingin some circumstances as appears from an explanation of the drain andfill phases of a PD treatment below.

In FIG. 6 is schematically shown a PD cycler 200 intended to be used inthe present invention. The PD cycler comprises a pressure chamber 201enclosing a heater bag 202 and a waste bag 203. The heater bag 202 isconnected to the outlet connector 139 of fluid sterilization device 100of FIG. 5 for receiving a fresh sterilized fluid for introduction intoheater bag 202. Heater bag 202 is connected with connector 139 by meansof a first tube 204 ending with a connector 205 mating with connector139 and comprising a valve 206. A second tube 207 connects heater bag202 with a connector 208 to a patient (not shown) and the second tube207 is controlled by a second valve 209. A third tube 210 connects thepatient connector 208 to the drain bag 203 by means of a third valve211. Finally, a fourth tube 212 connects drain bag 203 with a waste line213 by means of a valve 214. Heater bag 202 and drain bag 203 rest onscales 215 which monitor the combined weight of the two bags.

The operation of the PD cycler as schematically disclosed in FIG. 6,appears from the diagram of FIG. 7. The diagram indicates the fluidvolumes of the heater bag and drain bag during the different phases.

After priming, which is more fully described below, the first phase ofthe treatment is a drain phase, at the start of which the heater bag isfull of fluid, normally about 2.4 liters, and the drain bag is empty.The patient is connected and the third valve 211 is opened and asubpressure is exerted in pressure chamber 201. Fluid is withdrawn fromthe patient into drain bag 203 at a flow rate depending on the patientand the subpressure, normally from about 150 to 300 ml/min. When theperitoneal cavity of the patient is almost empty, which may be indicatedby a decrease of the drain flow as measured by the scales 215, the drainphase is terminated. The drain phase is normally from about 7 to 10minutes.

The second phase is a fill phase, in which the peritoneal cavity of thepatient is filled with fresh fluid contained in heater bag 202. Anoverpressure is exerted in pressure chamber 201 and valve 209 is opened,while the other valves are closed. The fill flow rate depends on thepatient and the overpressure and may be about 150 ml/min. The fill phaseis normally from about 10 to 15 minutes.

The third phase is the empty drain bag phase, in which an overpressureis exerted in the pressure chamber 201 and valve 214 is open. The fluidin the drain bag is directed to a waste line 213. The volumes are alwaysmonitored by the scales 215. The third phase may be about 2 minutes,since a high overpressure may be used and the flow restriction isminimal.

The fourth phase is heater bag fill with valve 206 open. In this case,normally a subpressure is exerted in the pressure chamber 201. Fluid isreceived from the sterilizing device 100 connected to connector 205 at aflow rate of about 120 ml/min. The fourth phase is normally from about15 to 17 minutes.

Thus, a complete cycle is from about 34 to 44 minutes. During a nighttreatment of 8 hours, it is possible to exchange from about 22 to28liters , in batches of 2 liters.

If it is desired to increase the fluid volume further, the times in thedifferent phases have to be shortened. It is noted that the heater bagfill time of from bout 15 to 17 minutes could be shortened by increasingthe flow rate of fluid from sterilizer 100. However, increasing the flowrate means considerable cost increases.

Instead it is noted that the flow rate of the fluid delivered fromsterilizer 100 is monitored by the sterilizer by flow meter 114 andweighing device 108. Thus, it is possible to fill the heater bag during(part of) the drain cycle as indicated by the broken line 216 in FIG. 7.This is done by opening valve 211 during the heater bag fill phase,before the heater bag fill phase is terminated, such as 10 minutes inadvance. If the drain phase is terminated before the heater bag isfilled, the drain phase has to be continued until the heater bag fillingis completed. However, it is no drawback to continue the drain phaselonger, since that only results in some further fluid being drained,which normally is an advantage. Since the flow from the sterilizer isknown, the PD cycler still has full control of the flow by using thereading from the scales and subtracting the inflow from the sterilizer.In this way, almost the complete drain phase can be saved in the cycletime, i.e. up to about 10 minutes.

Another way of saving time is to fill the heater bag during the emptydrain bag phase. It is recognised that the pressure chamber needs tohave an overpressure to empty the drain bag. However, the sterilizingdevice is able to deliver sterilized fluid under a slight overpressure.Thus, if valve 214 is open to pass fluid to the waste and valve 206 isopen to allow fluid to enter the heater bag, and if there is anoverpressure inside the pressure chamber, the heater bag may be filledduring the empty drain phase. Moreover, the pressure does not need to bereversed during the rest of the heater bag fill cycle, which normally isconsiderably longer than the empty drain bag phase. In this operationmode, it is still possible to keep accurate control over theultrafiltration, since the volume of fluid drained from the patient andthe volume of fluid filled into the patient are under full control ofthe mass balance device 215.

If the cycle time needs to be further shortened, that is possible by theaddition of a storage bag in the line set as indicated in FIG. 8. It isnoted that the sterilizer has to direct the sterilized fluid to thewaste 147 during the second phase filling the patient, when valve 206 isclosed, as well under the third phase emptying the drain bag.

In FIG. 8, the same components as in FIG. 6 have received the samereference numeral starting with 3 instead of 2. The inlet tube 304 isprovided with a branch line 316 ending in a storage bag 317. When valve306 is closed during the first, second and third phase, the sterilizer100 delivers PD solution into storage bag 317 through tube 316. Theheater bag 302 may then be filled much faster from the storage bag 317compared to the embodiment of FIG. 6. Thus, the heater bag fill phasemay be reduced to about 2 minutes or less. The efficiency of thecomplete device becomes dependent only on the cycler and its capacity todrain and fill the patient. The surplus time is merely 4 minutes, 2minutes for emptying of the drain bag and 2 minutes for filling theheater bag. The procedure has to be controlled if the sterilizer isoperated in the sequential mode as described in connection with FIG. 5,since the filling of heater bag has to start only when theconcentrations are correct in storage bag 317, i.e. after the completionof a complete fill cycle from the sterilizer.

The storage bag may also be used as an entry point for addition ofmedicaments or other additions, like insulin, antibiotic drugs,potassium chloride etc.

It is recognised that the PD solution produced according to thesterilizer in FIG. 5 will produce sterile bicarbonate fluid and enter itin the storage bag 317, and then produce sterile glucose solution andsubsequently enter that in the storage bag 317. Since the glucose fluidhas a low pH, some of the bicarbonate will react and form carbondioxide, which may be released as a gas. Thus, storage bag 317 isprovided with a valve and tube arrangement 318 to indicate when there issurplus gas in the storage bag 317 and expel it to the atmosphere.Another means for doing the same thing would be to include a sterilefilter or hydrophobic filter at the top of storage bag 317. The gas maybe expelled in a time interval when outlet valves 138 and 140 are opened(the position shown in FIG. 5) and pressure chamber 301 has anoverpressure and valve 306 is open to exert an overpressure into storagebag 317 and expel gas therein.

In the above example indicated in connection with FIG. 5, thebicarbonate concentrate was sterilized at a concentration of about 140mmol/liter (1000×20/140). However, there is a risk that carbon dioxideis formed during heat sterilization at such a concentration, and thus,the concentrate pump may be operated at a lower speed duringsterilization of bicarbonate fluid.

In FIG. 5, the concentrate fluid is preheated to quite a hightemperature. This is performed in an efficient heat exchanger 121 inwhich the heating fluid is the final sterilized fluid in the secondarycircuit of the heat exchanger. Thus, the heat exchanger cannot have anypoint with higher temperature than the sterilizing temperature, anddecomposition of the heat sensitive component is minimised. The furtherheating to the final sterilization temperature, i.e. from about 131° C.to about 141° C., takes place by the method of mixing with a fluidhaving a slightly higher temperature. Thus, the heat sensitive fluidcomponent is never exposed to harsh conditions, such as hot pointshaving excessively high temperatures, as may appear in an electricheater 123. Thus, favorable conditions for less formation of degradationproducts are obtained. The temperature difference between the primaryand secondary circuits of the heat exchanger is about 10° C., which ispossible to obtain without excessive long residence times in the heatexchanger.

In FIG. 5, there is a circuit not previously described for sterilizingthe equipment before use. In water line 115, a parallel circuit to valve120 and heat exchanger 121 is arranged comprising valve 150 and theprimary circuit of heat exchanger 143. When heat disinfection of thecomplete sterilizer 100 is to be performed before a treatment, valve 120is closed, valve 150 is opened and heater 123 is operated. The waterpasses from pump 117 by means of valve 150 to heat exchanger 143 andfurther to heater 123 to be heated to a temperature of, for example,141° C. The hot water passes heat exchanger 121 but is not cooledappreciably since the primary circuit of exchanger 121 is disconnectedand has no flow. The hot water after heat exchanger 121 passes throughline 133 and by means of valves 138 and 141 to heat exchanger 143 togive off its heat to the water passing at the primary side thereof.Finally, the water is discharged to the waste by means of restrictordevice, 145, which lowers the pressure from about 2 to 6 Bar toatmospheric pressure.

Thus, the on-line autoclave is self-sterilized and is ready forproducing PD fluids. The self-sterilizing step may be performed in about30 minutes and is initiated under program control to take place shortlybefore the start of a PD treatment, which is scheduled in advance by apatient. When the self-sterilization process is ready, the machineawaits the arrival of the patient, which connects a disposable set, suchas set 200 or 300, to the outlet connector 139. Then, the deviceproduces a quantity of sterile treatment fluid into the heater bag.However, before the patient is connected to connector 208, the tubesshould be filled with fluid to displace the air therein. This isperformed by attaching the connector 208 to a hook or attachment deviceon the cycler at approximately the same level as the heater bag. Then,valve 209 is opened to allow fluid to flow through tube 207 to patientconnector 208. The connector 208 is then ready for connection to thepatient.

It is appreciated that the priming procedure described above takes about20 minutes, since the heater bag must be filled with 2 liters ofsolution. If this time is too long for the patient to wait, it ispossible to perform a partial fill of the heater bag with, for example,5 dl solution produced in 4 minutes, and use this volume of fluid toprime the tubes and displace the air. Then, the patient may alreadyconnect himself to the connector 208 after 4 minutes of priming and thengo to bed, while the machine produces the first fill volume. It is notedthat there is normally about 2 to 4 dl of solution left in the heaterbag, in order to prevent complete emptying of the heater bag, becausethere is often some air or gas in the top of the heater bag, whichshould not be delivered to the patient. The first priming solution maybe different from the treatment solution, for example comprisingphysiological sodium chloride.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

What is claimed is:
 1. A method for sterilizing a heat sensitive fluidin a medical solution comprising providing a first heat sensitive fluidcomponent, providing a second fluid component, heating said second fluidcomponent to a first temperature, said first temperature being greaterthan a predetermined sterilizing temperature, mixing said first heatsensitive fluid component with said heated second fluid component,whereby said first heat sensitive fluid component is heated and saidheated second fluid component is cooled, and a mixed fluid is providedat a second temperature, said second temperature being at least saidpredetermined sterilizing temperature, and maintaining said mixed fluidat said second temperature for a predetermined sterilizing period,whereby a predetermined sterilizing dose is obtained for delivery to arecipient.
 2. The method of claim 1 including controlling said heatingof said second fluid component to said first temperature to ensure thatsaid mixed fluid reaches said second temperature.
 3. The method of claim1 including cooling said mixed fluid.
 4. The method of claim 1 whereinsaid first heat sensitive fluid component comprises a component selectedfrom the group consisting of glucose and a glucose polymer.
 5. Themethod of claim 1 wherein said second fluid component comprises water.6. The method of claim 5 wherein said second fluid component includeselectrolytes.
 7. The method of claim 6 wherein said electrolytes areselected from the group consisting of sodium chloride, calcium chloride,magnesium chloride, potassium chloride, sodium bicarbonate, and sodiumlactate.
 8. The method of claim 1 including preheating said first heatsensitive fluid component.
 9. The method of claim 1 includingmaintaining said first heat sensitive fluid component and said secondfluid component under a predetermined pressure sufficient to preventboiling of said first heat sensitive fluid component and said secondfluid component.
 10. The method of claim 9 wherein said providing ofsaid first heat sensitive fluid component and providing of said secondfluid component comprises providing flows of said fluid components. 11.The method of claim 10 wherein said flow of said first heat sensitivefluid component comprises a first flow rate and said flow of said secondfluid component comprises a second flow rate, said second flow ratebeing greater than said first flow rate.
 12. The method of claim 10including determining said first and second flow rates by means of aweighing device or a flow meter, and maintaining said first heatsensitive fluid component and said second fluid component at saidpredetermined pressure by means of a pump.
 13. The method of claim 10wherein said heat sensitive fluid component comprises a complex fluidcomprising a plurality of first fluid components including said firstheat sensitive fluid component, and including sequentially sterilizingsaid plurality of first fluid components.
 14. The method of claim 13including providing a plurality of sources of concentrate fluidcomponents for each of said plurality of first fluid components,providing a source of said second fluid component, said second fluidcomponent comprising water, pumping one of said plurality of sources ofsaid concentrate fluid components so as to increase the pressurethereof, pumping said water so as to increase the pressure thereof, andrepeating said method for each of said plurality of first fluidcomponents.
 15. The method of claim 14 including preheating each of saidplurality of first fluid components before said mixing with said heatedsecond fluid component.
 16. The method of claim 15 wherein saidpreheating comprises heat exchanging each of said plurality of saidfirst fluid components with said predetermined sterilized dose.
 17. Themethod of claim 16 wherein said preheating comprises initially heatingsaid second fluid component by heat exchange with said predeterminedsterilized dose, and further preheating said second fluid component tosaid first temperature by means of a separate heater.
 18. The method ofclaim 17 wherein said separate heater comprises an electric heater. 19.The method of claim 18 including controlling said further preheating ofsaid second fluid component by means of a temperature sensor downstreamof said maintaining of said mixed fluid at said second temperature,whereby said second temperature is maintained at said at least saidpredetermined sterilizing temperature.
 20. The method of claim 1including dissolving at least one powdered substance in said secondfluid component to provide at least one of said first heat sensitivefluid components and said second fluid component.
 21. The method ofclaim 1 including providing a third heat sensitive fluid component, andmixing said first heat sensitive fluid component and said third heatsensitive fluid component with said heated second fluid component. 22.The method of claim 21 wherein said third heat sensitive fluid componentcomprises water and at least one amino acid.
 23. Apparatus forsterilizing a heat sensitive fluid in a medical solution comprising afirst vessel containing a first heat sensitive fluid component, a secondvessel containing a second fluid component, a first heater for heatingsaid second fluid component to a first temperature, said firsttemperature being greater than a predetermined sterilizing temperature,mixing means for mixing said first heat sensitive fluid component withsaid second fluid component to obtain a mixed fluid at a secondtemperature at least equal to said predetermined sterilizingtemperature, and residence means for maintaining said mixed fluid atsaid second temperature for a predetermined sterilizing period, wherebya sterilized fluid is provided for delivery to a recipient.
 24. Theapparatus of claim 23 including a controller for controlling said firstheater to obtain said first temperature.
 25. The apparatus of claim 23including a cooler for cooling said mixed fluid.
 26. The apparatus ofclaim 23 wherein said first heat sensitive fluid component comprises acomponent selected from the group consisting of glucose and a glucosepolymer.
 27. The apparatus of claim 23 wherein said second fluidcomponent comprises water.
 28. The apparatus of claim 27 wherein saidsecond fluid component includes an electrolyte.
 29. The apparatus ofclaim 28 wherein said electrolyte is selected from the group consistingof sodium chloride, calcium chloride, magnesium chloride, potassiumchloride, sodium bicarbonate and sodium lactate.
 30. The apparatus ofclaim 23 including a preheater for preheating said first heat sensitivefluid component.
 31. The apparatus of claim 23 including pressurizingmeans for maintaining said first heat sensitive fluid component and saidsecond fluid component at a predetermined pressure to prevent said firstheat sensitive fluid component and said second fluid component fromboiling.
 32. The apparatus of claim 23 wherein said first heat sensitivefluid component and said second fluid component comprise fluid flows.33. The apparatus of claim 32 wherein said fluid flow of said first heatsensitive fluid component has a first flow rate and said fluid flow ofsaid second fluid component has a second flow rate, said second flowrate being greater than said first flow rate.
 34. The apparatus of claim33 including flow rate determining means for determining said first andsecond flow rates, said pressurizing means comprising a pump.
 35. Theapparatus of claim 34 wherein said flow rate determining means comprisesa weighing device or a flow meter.
 36. The apparatus of claim 32 whereinsaid first heat sensitive fluid component comprises a plurality of firstfluid components including said first heat sensitive fluid component,and including means for sequentially sterilizing each of said pluralityof first fluid components and said second fluid component.
 37. Theapparatus of claim 36 wherein said means for sequentially sterilizingincludes supply means for supplying said plurality of first fluidcomponents, said first vessel comprising a plurality of containers forconcentrates of said plurality of first fluid components, said secondvessel comprising an inlet for said second fluid component, aconcentrate pump for pumping one of said plurality of first fluidcomponents from one of said plurality of containers whereby the pressureof said one of said first fluid components is increased, a water pumpfor pumping said second fluid component, said second fluid componentcomprising water, whereby the pressure of said second fluid component isincreased, said heater comprising a water heater for heating said secondfluid component to said first temperature, said mixing means comprisinga mixer for mixing said one of said plurality of first fluid componentsand said heated second fluid component to provide said mixed fluid, saidresidence means comprising means for maintaining said mixed fluid atsaid first temperature for a predetermined sterilizing period to providea sterilized dose for delivery to a recipient, and including controlmeans for controlling and repeating said sequential sterilizing of eachof said plurality of first fluid components to provide a finalsterilized complex fluid.
 38. The apparatus of claim 37 includingpreheating means for preheating said one of said plurality of firstfluid components.
 39. The apparatus of claim 38 including a heatexchanger for recovering heat from said sterilized dose.
 40. Theapparatus of claim 39 wherein said heat exchanger preheats said secondfluid component by heat exchange with said sterilized dose, andincluding a heater for heating said second fluid component to said firsttemperature.
 41. The apparatus of claim 40 including a temperaturesensor downstream of said residence means for controlling said heater,whereby said first temperature comprises a temperature at leastsufficient to constitute said sterilizing temperature.
 42. The apparatusof claim 23 wherein at least one of said first and second vesselsincludes at least one powdered substance for dissolution in water toprovide at least one of said first and second fluids.
 43. The apparatusof claim 23 including a third vessel for containing a third heatsensitive fluid component.
 44. The apparatus of claim 43 wherein saidthird heat sensitive fluid component comprises water and at least oneamino acid.